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Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.

Jiang XX, Chou Y, Jones L, Wang T, Sanchez S, Huang XF, Zhang L, Wang C, Chen SY - Sci Rep (2015)

Bottom Line: In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens.Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci.Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, USA.

ABSTRACT
B cell-mediated antibody response plays critical roles in protective immunity, as well as in the pathogenesis of allergic and autoimmune diseases. Epigenetic histone and DNA modifications regulate gene transcription and immunity; however, so far, little is known about the role of epigenetic regulation in antibody responses. In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens. We revealed that MYSM1 intrinsically represses plasma cell differentiation and antibody production. Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci. Hence, this study uncovers a critical role for MYSM1 in epigenetically repressing plasma cell differentiation and antibody production, in addition to its opposing, active role in B cell development. Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.

No MeSH data available.


Related in: MedlinePlus

MYSM1 occupies the Pax5 loci in naive B cells.(a) Schematic diagram of Pax5 gene and its promoter and enhancer region illustrating the positions of the primer pairs used for ChIP assays. (b) ChIP assays of naïve splenic WT B220+ cells (nB, left), LPS-activated WT B220+CD138− cells (aB, middle), and WT CD138+B220− plasma cells (PC, right) using a MYSM1 antibody or control IgG probing for the Pax5 locus. Quantitative PCR was used to analyze the enrichment and the fold enrichments are represented from one of three independent experiments. **p < 0.01, IgG vs. MYSM1.
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f6: MYSM1 occupies the Pax5 loci in naive B cells.(a) Schematic diagram of Pax5 gene and its promoter and enhancer region illustrating the positions of the primer pairs used for ChIP assays. (b) ChIP assays of naïve splenic WT B220+ cells (nB, left), LPS-activated WT B220+CD138− cells (aB, middle), and WT CD138+B220− plasma cells (PC, right) using a MYSM1 antibody or control IgG probing for the Pax5 locus. Quantitative PCR was used to analyze the enrichment and the fold enrichments are represented from one of three independent experiments. **p < 0.01, IgG vs. MYSM1.

Mentions: Further, we tested the possibility that MYSM1 may directly activate the transcription of Pax5 in mature B cells as well. We first examined the association of MYSM1 with the Pax5 locus by ChIP assays with a panel of primer pairs corresponding to the promoter and enhancer regions of the Pax5 locus. Figure 6a,b show that MYSM1 was associated with the promoter region of the Pax5 locus in naïve B cells, suggesting a direct role of MYSM1 in Pax5 transcription. When comparing the occupancy of MYSM1 at the Pax5 locus during plasma cell differentiation, we unexpectedly found that the occupancy of MYSM1 at the Pax5 locus was drastically reduced in activated B cells and plasma cells (Fig. 6b). Together these unexpected observations imply that MYSM1 occupies the Pax5 loci in naïve B cells, but dissociates from the target loci during B cell activation and plasma cell differentiation either due to the reduced MYSM1 expression, as observed in Fig. 5e, or other unknown reasons.


Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.

Jiang XX, Chou Y, Jones L, Wang T, Sanchez S, Huang XF, Zhang L, Wang C, Chen SY - Sci Rep (2015)

MYSM1 occupies the Pax5 loci in naive B cells.(a) Schematic diagram of Pax5 gene and its promoter and enhancer region illustrating the positions of the primer pairs used for ChIP assays. (b) ChIP assays of naïve splenic WT B220+ cells (nB, left), LPS-activated WT B220+CD138− cells (aB, middle), and WT CD138+B220− plasma cells (PC, right) using a MYSM1 antibody or control IgG probing for the Pax5 locus. Quantitative PCR was used to analyze the enrichment and the fold enrichments are represented from one of three independent experiments. **p < 0.01, IgG vs. MYSM1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4562257&req=5

f6: MYSM1 occupies the Pax5 loci in naive B cells.(a) Schematic diagram of Pax5 gene and its promoter and enhancer region illustrating the positions of the primer pairs used for ChIP assays. (b) ChIP assays of naïve splenic WT B220+ cells (nB, left), LPS-activated WT B220+CD138− cells (aB, middle), and WT CD138+B220− plasma cells (PC, right) using a MYSM1 antibody or control IgG probing for the Pax5 locus. Quantitative PCR was used to analyze the enrichment and the fold enrichments are represented from one of three independent experiments. **p < 0.01, IgG vs. MYSM1.
Mentions: Further, we tested the possibility that MYSM1 may directly activate the transcription of Pax5 in mature B cells as well. We first examined the association of MYSM1 with the Pax5 locus by ChIP assays with a panel of primer pairs corresponding to the promoter and enhancer regions of the Pax5 locus. Figure 6a,b show that MYSM1 was associated with the promoter region of the Pax5 locus in naïve B cells, suggesting a direct role of MYSM1 in Pax5 transcription. When comparing the occupancy of MYSM1 at the Pax5 locus during plasma cell differentiation, we unexpectedly found that the occupancy of MYSM1 at the Pax5 locus was drastically reduced in activated B cells and plasma cells (Fig. 6b). Together these unexpected observations imply that MYSM1 occupies the Pax5 loci in naïve B cells, but dissociates from the target loci during B cell activation and plasma cell differentiation either due to the reduced MYSM1 expression, as observed in Fig. 5e, or other unknown reasons.

Bottom Line: In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens.Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci.Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, USA.

ABSTRACT
B cell-mediated antibody response plays critical roles in protective immunity, as well as in the pathogenesis of allergic and autoimmune diseases. Epigenetic histone and DNA modifications regulate gene transcription and immunity; however, so far, little is known about the role of epigenetic regulation in antibody responses. In this study, we found that mice deficient in the histone H2A deubiquitinase MYSM1, despite their severe defect in B cell development, exhibit an enhanced antibody response against both T cell-dependent and independent antigens. We revealed that MYSM1 intrinsically represses plasma cell differentiation and antibody production. Mechanistic studies demonstrated that MYSM1 is a transcriptional activator of Pax5, the repressors of plasma cell differentiation, by facilitating key transcriptional factor recruitment and coordinating histone modifications at the Pax5 loci. Hence, this study uncovers a critical role for MYSM1 in epigenetically repressing plasma cell differentiation and antibody production, in addition to its opposing, active role in B cell development. Importantly, this study further provides a new target and strategy to modulate antibody production and responses with profound therapeutic implications.

No MeSH data available.


Related in: MedlinePlus